This invention relates to compounds which are xcex11A agonists, pharmaceutical compositions containing these compounds, and methods of treatment using these compounds.
The xcex11 adrenoceptor plays a part in the sympathetic maintenance of smooth muscle tone and xcex11-adrenergic agonists are known to increase muscle tone in the lower urinary tract (Testa, R. Eur. J. Pharmacol. (1993) 249, 307-315). Phenylpropanolamine (Cummings, J. M. Drugs of Today (1996) 32, 609-614) and midodrine are xcex11 agonists which have been used for the treatment of urinary incontinence. These agents act by stimulating the xcex11 receptors present in the urethra and bladder neck (trigone) leading to an increase in intraurethral pressure. However, these agents suffer from cardiovascular related side effects (Taniguchi, N. Eur. J. Pharmacol. (1996) 318, 117-122). Thus an agent that is effective in the treatment of urinary incontinence without cardiovascular side effects is needed.
At least 3 subtypes of the xcex11 adrenoceptor (xcex11A, xcex11B, and xcex11D) have been identified via pharmacological techniques. The corresponding molecular clones (xcex11a, xcex11b, xcex11d) have been identified (Hancock, A. H. Drug Development Research (1996) 39, 54-107). Studies have shown that the xcex11A receptor is present in the lower urinary tract (Testa, R. Eur. J. Pharmacol. (1993) 249, 307-315). The xcex11A subtype has been shown to be the predominant subtype in the urethra (Takahashi, H. Neurourol. Urodyn. (1996), 15, 342-343).
Urinary stress incontinence is the involuntary loss of urine due to a stress such as coughing, sneezing, bending or lifting heavy objects. This condition may occur due to a weakening in the ability of the urethra to constrict. Selective stimulation of the xcex11A receptor can result in the contraction of the bladder neck (trigone) and urethra leading to an increase in urethral pressure with reduced blood pressure effects. The compounds of the present invention are selective xcex11A agonists which may preferentially increase intraurethral pressure relative to nonselective xcex11 agonists such as midodrine and phenylpropanolamine. Therefore, these agents may be useful for the treatment of urinary incontinence.
FR 2768054-A1 and FR 2768055-A1 disclose a series of sulfonamides and sulfonanilides as agents which constrict trigonal smooth muscle and are claimed to be useful for the treatment of ejaculation disorders, especially retrograde ejaculation or aspermia. The compounds of the present invention may be also usefull for the treatment of ejaculatory disorders.
The compounds of the present invention may be useful for the treatment of nasal decongestion (Proctor Pharmac. Ther. B. (1976) 2, 493-509) and septic shock (Cole, L. Blood Purif (1997) 15, 309-318).
EP 0717037 A1 discloses a group of 4-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazoles that are claimed as xcex12 agonists and xcex11 antagonists for the treatment of ischemia and hypertension. Imidazole compounds that are xcex12-adrenergic ligands are disclosed in (Zhang, et. al. J. Med. Chem (1997) 40, 3014-4024). The compounds of the present invention are structurally and pharmacologically distinct from EP 0717037 A1 and Zhang, et. Al.
WO 99/05115 discloses a group of substituted imidazole derivatives that are claimed as H3 (histamine-3) receptor ligands potentially useful as sedatives, as sleep regulators, as anticonvulsants, as regulators of hypothalamo-hypophyseal secretion, as antidepressants, as modulators of cerebral circulation, in the treatment of asthma, in the treatment of irritable bowel syndrome and as tools in the study of the role of histamine.
EP 0887346 A2 discloses a group of 4-imidazole derivatives of phenyl-alkylsulfonamides as xcex11A/1L adrenoceptor agonists for the treatment of urinary incontinence and nasal decongestion.
In its principle embodiment, the present invention discloses compounds having formula I: 
or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein
R1 is selected from the group consisting of xe2x80x94S(O)2R9 and xe2x80x94C(O)R10;
R9 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and xe2x80x94NZ1Z2 wherein Z1 and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl;
R10 is selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, and xe2x80x94NZ1Z2;
R2 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, halo, haloalkyl, and hydroxy;
R3 is selected from the group consisting of hydrogen, alkenyloxy, alkyl, alkoxy, alkoxyalkyl, alkynyloxy, arylalkyl, cycloalkylalkyl, haloalkyl, and hydroxy;
R4 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, and hydroxy; or
R3 and R4 together with the carbon atoms to which they are attached form a 5-, 6-, or 7-membered carbocyclic ring; or
R3 and R4 together with the carbon atoms to which they are attached form a 5- or 6-membered ring containing 1 heteroatom selected from the group consisting of O, NR11, and S(O)n;
R11 is selected from the group consisting of hydrogen, alkenyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, arylalkyl, formyl, xe2x80x94C(O)NZ1Z2, and xe2x80x94SO2NZ1Z2;
n is 0-2;
R5 is selected from the group consisting of imidazol-4-yl, imidazol-5-yl, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, triazole, thiadiazole, pyridine, pyrimidine, pyrazine, and pyridazine optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, hydroxy, lower alkoxy, lower alkyl, xe2x80x94NZ1Z2, (NZ1Z2)alkyl, xe2x80x94C(O)NZ1Z2, and xe2x80x94SO2NZ1Z2;
R6 is selected from the group consisting of hydrogen, alkoxy, alkyl, halo, haloalkyl, and hydroxy;
R7 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and haloalkyl; and
R8 is selected from the group consisting of hydrogen and alkyl; or
R3 and R8 together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered carbocyclic ring; or
R3 and R8 together form 
R12 and R15 are independently selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl; or
R12 and R15 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic ring; or
R12 and R4 together with the carbon atoms to which they are attached form a 5-, 6-, or 7-membered carbocyclic ring;
provided that when R12 and R4 together with the carbon atoms to which they are attached form a 5-, 6-, or 7-membered carbocyclic ring then R15 is hydrogen; or
R12 and R4 together with the carbon atoms to which they are attached form a 5- or 6-membered ring containing 1 heteroatom selected from the group consisting of O, NR11, and S(O)n;
provided that when R12 and R4 together with the carbon atoms to which they are attached form a 5- or 6-membered ring containing 1 heteroatom selected from the group consisting of O, NR11, and S(O)n, then R15 is hydrogen.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I-X or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of treating ejaculatory dysfunction including, but not limited, to retrograde ejaculation comprising administering a therapeutically effective amount of a compound of formula I-X or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof
Yet another embodiment of the invention relates to a method urinary incontinence comprising administering a therapeutically effective amount of a compound of formula I-X or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.